Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial . (5th July 2022)

• Record Type: Journal Article
• Authors: Doehner, Wolfram; Anker, Stefan D; Butler, Javed; Zannad, Faiez; Filippatos, Gerasimos; Ferreira, João Pedro; Salsali, Afshin; Kaempfer, Carolyn; Brueckmann, Martina; Pocock, Stuart J; Januzzi, James L; Packer, Milton
• Is Part Of: European heart journal. Volume 43:Number 36(2022)
• Page Start: 3435
• Page End: 3446
• Publication Date: 2022-07-05
• Subjects: Heart failure with reduced ejection fraction -- Empagliflozin -- Uric acid -- Metabolism -- Hospitalization -- Outcome; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac320
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. Methods: The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. Results: Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28–2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35–2.91); all-cause mortality, HR 1.8 (95% CI 1.29–2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: −1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52–0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65–0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69–0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA ( P for interaction = 0.005 and = 0.011, respectively). Conclusion: Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA. Structured Graphical Abstract: Structured Graphical Abstract Elevated serum uric acid (SUA) relates to adverse outcome in HF with reduced ejection fraction (HFrEF), but empagliflozin significantly reduces SUA and clinically relevant hyperuricaemia. *Hazard ratio shown for the primary composite endpoint using cubic splines (4 knots), multivariable adjusted analysis. †Clinically relevant hyperuricaemia is defined as the composite episodes of acute gout, gouty arthritis or the initiation of treatment with SUA lowering therapy (xanthine oxidase inhibitors, uricosuric agents or colchicine). ‡Tertiles of SUA: Male: T1 = 6.3 mg/dL, T2 = 8.0 mg/dL; Female: T1 = 5.5 mg/dL, T2 = 7.2 mg/dL. Cox regression models included age, sex, geographical region, diabetes status, left ventricular ejection fraction, and estimated glomerular filtration rate (CKD-EPI)and SUA subgroup and SUA subgroup*treatment interaction for the subgroup analyses.